AUTHOR=Trägårdh Magnus , Chappell Michael J. , Palm Johan E. , Evans Neil D. , Janzén David L. I. , Gennemark Peter TITLE=Input Estimation for Extended-Release Formulations Exemplified with Exenatide JOURNAL=Frontiers in Bioengineering and Biotechnology VOLUME=5 YEAR=2017 URL=https://www.frontiersin.org/journals/bioengineering-and-biotechnology/articles/10.3389/fbioe.2017.00024 DOI=10.3389/fbioe.2017.00024 ISSN=2296-4185 ABSTRACT=

Estimating the in vivo absorption profile of a drug is essential when developing extended-release medications. Such estimates can be obtained by measuring plasma concentrations over time and inferring the absorption from a model of the drug’s pharmacokinetics. Of particular interest is to predict the bioavailability—the fraction of the drug that is absorbed and enters the systemic circulation. This paper presents a framework for addressing this class of estimation problems and gives advice on the choice of method. In parametric methods, a model is constructed for the absorption process, which can be difficult when the absorption has a complicated profile. Here, we place emphasis on non-parametric methods that avoid making strong assumptions about the absorption. A modern estimation method that can address very general input-estimation problems has previously been presented. In this method, the absorption profile is modeled as a stochastic process, which is estimated using Markov chain Monte Carlo techniques. The applicability of this method for extended-release formulation development is evaluated by analyzing a dataset of Bydureon, an injectable extended-release suspension formulation of exenatide, a GLP-1 receptor agonist for treating diabetes. This drug is known to have non-linear pharmacokinetics. Its plasma concentration profile exhibits multiple peaks, something that can make parametric modeling challenging, but poses no major difficulties for non-parametric methods. The method is also validated on synthetic data, exploring the effects of sampling and noise on the accuracy of the estimates.